Ketone alkylation poses a problem in regioselectivity

Ketones are unique because they can have enolizable protons on both sides of the carbonyl group. Unless the ketone is symmetrical, or unless one side of the ketone happens to have no enolizable protons, two regioisomers of the enolate are possible and alkylation can occur on either side to give regioisomeric products. We need to be able to control which enolate is formed if ketone alkylations are to be useful. 

Selective enolate formation is straightforward if the protons on one side of the ketone are significantly more acidic than those on the other. This is what you have just seen with ethyl acetoacetate it is a ketone, but with weak bases (pKaH 18) it only ever enolizes on the side where the protons are acidified by the second electron-withdrawing group. If two new substituents are introduced, in the manner you have just seen, they will always both be joined to the same carbon atom. This is an example of thermodynamic control only the more stable of the two possible enolates is formed. 

This principle can be extended to ketones whose enolates have less dramatic differences in stability. We said in Chapter 21 that, since enols and enolates are alkenes, the more substituents they carry the more stable they are. So, in principle, even additional alkyl groups can control enolate formation under thermodynamic control. Formation of the more stable enolate requires a mechanism for equilibration between the two enolates, and this must be proton transfer. If a proton source is available— and this can even be just excess ketone—an equilibrium mixture of the two enolates will form. The composition of this equilibium mixture depends very much on the ketone but, with 2-phenylcyclo-hexanone, conjugation ensures that only one enolate forms. The base is potassium hydride it s strong, but small, and can be used under conditions that permit enolate equilibration. 

The more substituted lithium enolates can also be formed from the more substituted silyl enol ethers by substitution at silicon—a reaction you met in Chapter 21. The value of this reaction now becomes clear, because the usual way of making silyl enol ethers (Me3SiCl, Et3N) typically produces, from unsymmetrical ketones, the more substituted of the two possible ethers. 

An alternative view is that reaction takes place through the enol the Si-0 bond is so strong that even neutral enols react with Me3SiCl, on oxygen, of course. The predominant enol is the more substituted, leading to the more substituted silyl enol ether. 

OEt introduction of both new substituents directed by ester group 

The influence of substituents on the stability of alkenes was discussed on p. 394. The fact that more substituted enols are more stable was discussed in Chapter 20, p. 465. 

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